Methods of treating prader-willi syndrome

ABSTRACT

Methods of treating Prader-Willi syndrome in a subject in need of treatment are provided. The methods include administering to the subject an effective amount of a compound of Formula I, 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein R, R′, X, Y and Z are defined as set forth in the specification. In embodiments, an effective amount of captodiamine or a pharmaceutically acceptable salt thereof is administered to the subject.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of, and priority to, U.S.Provisional Patent Application No. 62/154,875 filed on Apr. 30, 2015,the entire contents of which are incorporated by reference herein.

TECHNICAL FIELD

Methods of treating Prader-Willi Syndrome.

BACKGROUND

Prader-Willi syndrome (PWS) is a genetic disease caused by lack ofexpression of genes from an imprinted region of the paternally inheritedchromosome 15q11-q13, near the centromere (Aycan and Bas, J Clin ResPediatr Endocrinol, 6(2):62-67 (2014)). The frequency of the disease isbetween about 1/10,000 and 1/30,000 with approximately 400,000 PWSpatients living worldwide. PWS is a spectrum disorder which affects manysystems in the body. Subjects with PWS typically suffer from a host ofsymptoms including neurologic, cognitive, endocrine, and behavioralabnormalities. Initially, infants exhibit hypotonia (floppy babysyndrome) and experience difficulty in sucking and feeding which canlead to growth delay. Subjects with PWS frequently have poor muscletone, growth hormone deficiency, low levels of sex hormones, a constantfeeling of hunger and excessive appetite (hyperphagia). They overeat,leading to weight gain, obesity and a high incidence of diabetes. Othersigns appear including short stature, poor motor skills, underdevelopedsex organs, and mild intellectual and learning disabilities. PWSsubjects may experience delayed speech and language development, andinfertility. Behavioral symptoms may include cognitive impairment,cognitive rigidity, emotional lability and obsessive-compulsivebehavior, with autistic symptomology, psychotic episodes, and biopolardisorder with psychosis. Additional clinical manifestations may includeexcessive daytime sleepiness, scoliosis, osteopenia/osteoporosis,decreased gastrointestinal motility, sleep disturbances, and reducedpain sensitivity.

PWS is the most common genetic neurodevelopmental disorder associatedwith obesity. Data indicates that PWS is associated with an approximate50% reduction in plasma BDNF levels normalized to body weight (Han etal., J. Clin. Endo. Metab., 95, 3532-36 (2010)). Studies also show thatselectively up-regulating BDNF in the hypothalamus inhibits appetite andweight gain in mice on a high fat diet, and at very high levels ofexpression using viral vector gene transfer causes severe weight loss innormal control chow fed mice (Cao, et al., Nat Med., 15(4):447-54(2009)). BDNF appears to act downstream to other modulators of feeding,notably leptin and the MC4 receptor.

There is currently no cure for PWS. Growth hormone, exercise, anddietary supervision can help build muscle mass and control weight.Treatment with human growth hormone starting by 2 years of age has beenreported to improve body composition, motor function, height, and lipidprofiles. See, Carrel et al., J Clin Endocrinol Metab 95(3):1131-1136(2010 March). Other treatments may include oxytocin, sex hormones andbehavior therapy. However, most people with PWS will need specializedcare and supervision throughout their lives. There remains a need forimproved and/or additional therapies for treating PWS.

Captodiamine (also known as captodiame)(2-[(4-butylsulfanylphenyl)-phenyl-methyl]sulfanyl-N,N-dimethylethanamine)was developed in the 1950's and is a derivative of the antihistaminediphenhydramine. Captodiamine was identified in a class of compoundsdesignated as sedatives and antispasmodics. See, e.g., U.S. Pat. No.2,830,083, incorporated herein by reference. It was subsequentlydeveloped for treatment of anxiety disorders and marketed as ananxiolytic. The drug is not a potent hypnotic and appeared to be safeand well tolerated. Although no formal double blind randomized studieswere carried out on captodiamine when it was initially marketed, it waswidely prescribed.

Captodiamine was marketed as SUVREN® by Ayerst at the timenotwithstanding the fact that there was a paucity of published studies.In the early 1960's the FDA DESI (Drug Evaluation & Safety Initiative)program was implemented, i.e., drugs which did not have compellingevidence of efficacy, strong proponents, or external champions, wereessentially struck off the register, or removed from the approved list.Captodiamine was one such drug, and essentially disappeared.

In 1999, a comparative study on the effects of captodiamine andlorazepam on car driving ability was conducted (Mercier-Guyon, et al.,Clin Drug Invest, 17 (6): 451-459 (1999)). Captodiamine, as compared tolorazepam, reportedly improved the concentration and dexterity ofindividuals when driving, without inducing a tendency to drowsiness. Inanother study, captodiamine treatment was associated with lower severityof benzodiazepine withdrawal symptoms as compared to placebo(Mercier-Guyon et al., Curr Med Res Opin., 20(9):1347-1355 (2004)).

In 2013, a group from University College Dublin, published a paper inwhich they reported that captodiamine had activity as a sigma-1 receptoragonist as well as a 5-HT_(2c) antagonist and dopamine D3 agonist (Ringand Regan, Journal of Psychopharmacology, 27(10):930-939 (2013)).Captodiamine was shown to increase brain-derived neurotrophic factor(BDNF) protein levels in the hypothalamus, but not in the cortex or thehippocampus. U.S. Pat. No. 8,461,389 describes use of captodiamine inthe treatment of anxiety and/or depression associated with an affectivedisorder and/or symptoms associated with cognitive impairment disorder.

SUMMARY

Methods of treating Prader-Willi Syndrome are provided and, inembodiments, include administering to a subject in need thereof apharmaceutical composition including an effective amount of a compoundof Formula I,

wherein X is an ethylene, propylene, butylene or pentylene group; R isC₁₋₉ alkyl, preferably C₁₋₅ alkyl; R′ is C₁₋₉ alkyl, alkenyl or alkynyl;Y is hydrogen, halide such as chloro, fluoro, iodo or bromo,hydroxyC₁₋₄alkyl, amino, C₁₋₄alkylamino, acetylamino or thio; and Z ishydrogen, halide such as chloro, fluoro, iodo or bromo, hydroxyC₁₋₄alkyl, amino, C₁₋₄ alkylamino, acetylamino or thio, or apharmaceutically acceptable salt thereof.

In embodiments, X may be an ethylene, propylene, butylene, or pentylenegroup and R is methyl, R′ is butyl, Y is hydrogen and Z is hydrogen; orR is C₁₋₉ alkyl, C₁₋₅ alkyl, and R′ is butyl, X is ethylene, Y ishydrogen and Z is hydrogen.

In embodiments, Y may be hydrogen, halide such as chloro, fluoro, iodoor bromo, hydroxyC₁₋₄alkyl, amino, C₁₋₄alkylamino, acetylamino, thio andR is methyl, R′ is butyl, X is ethylene and Z is hydrogen.

In embodiments, Z may be hydrogen, halide such as chloro, fluoro, iodoor bromo, hydroxyC₁₋₄alkyl, amino, C₁₋₄alkylamino, acetylamino, thio andR is methyl, R′ is butyl, X is ethylene and Y is hydrogen.

In embodiments, R′ may be C₁₋₉ alkyl, alkenyl or alkynyl and R ismethyl, X is ethylene, Y is hydrogen and Z is hydrogen.

In embodiments, methods of treating Prader-Willi Syndrome includeadministering to a subject in need thereof a pharmaceutical compositionincluding an effective amount of a compound of Formula II,

also known as2-[(4-butylsulfanylphenyl)-phenylmethyl]sulfanyl-N,N-dimethylethanamine(captodiamine), or a pharmaceutically acceptable salt thereof.

In embodiments, a composition including from 0.1 mg to 1500 mg ofcompound of Formula 1 or a pharmaceutically acceptable salt thereof isadministered within a 24-hour period. In embodiments, a compositionincluding a compound of Formula 1 or a pharmaceutically acceptable saltthereof is administered from one to four times a day. In embodiments,administering a composition including a compound of Formula I or apharmaceutically acceptable salt thereof is accomplished via one or moreof the following routes: oral, buccal, sublingual, rectal, topical,intranasal, vaginal, and parenteral. In embodiments, administering acomposition including a compound of Formula I or a pharmaceuticallyacceptable salt thereof provides improvement in at least one of thefollowing symptoms: hypotonia, difficulty in sucking, difficulty infeeding, poor muscle tone, growth hormone deficiency, low levels of sexhormones, a constant feeling of hunger, excessive appetite(hyperphagia), weight gain, obesity, short stature, poor motor skills,underdeveloped sex organs, intellectual disability, learning disability,delayed speech development, delayed language development, infertility,cognitive impairment, cognitive rigidity, emotional lability,self-injury, obsessive-compulsive behavior, autistic symptomology,psychotic episodes, bipolar disorder with psychosis, excessive daytimesleepiness, scoliosis, osteopenia/osteoporosis, decreasedgastrointestinal motility, sleep disturbances, and/or reduced painsensitivity.

In embodiments, the subject is administered a composition including 0.1mg to 1500 mg of captodiamine or a pharmaceutically acceptable saltthereof. In embodiments, the subject is administered a compositionincluding 1 mg to 500 mg of captodiamine or a pharmaceuticallyacceptable salt thereof. In embodiments, the subject is administered acomposition including 50 mg to 250 mg of captodiamine or apharmaceutically acceptable salt thereof. In embodiments, a compositionincluding from 1 mg to 1500 mg of captodiamine or a pharmaceuticallyacceptable salt thereof is administered within a 24-hour period. Inembodiments, the total amount of captodiamine or a pharmaceuticallyacceptable salt thereof administered to the subject in a twenty-fourhour period is between 1 mg and 1500 mg. In embodiments, the totalamount of captodiamine or a pharmaceutically acceptable salt thereofadministered to the subject in a twenty-four hour period is between 1 mgand 500 mg. In embodiments, a composition including captodiamine or apharmaceutically acceptable salt thereof is administered from one tofour times a day.

In embodiments, administering a composition including captodiamine or apharmaceutically acceptable salt thereof is accomplished via one or moreof the following routes: oral, buccal, sublingual, rectal, topical,intranasal, and parenteral. In embodiments, administering a compositionincluding captodiamine or a pharmaceutically acceptable salt thereofprovides improvement in at least one of the following symptoms:hypotonia, difficulty in sucking, difficulty in feeding, poor muscletone, growth hormone deficiency, low levels of sex hormones, a constantfeeling of hunger, excessive appetite (hyperphagia), weight gain,obesity, short stature, poor motor skills, underdeveloped sex organs,intellectual disability, learning disability, delayed speechdevelopment, delayed language development, infertility, cognitiverigidity, emotional lability, obsessive-compulsive behavior, autisticsymptomology, psychotic episodes, bipolar disorder with psychosis,excessive daytime sleepiness, scoliosis, osteopenia/osteoporosis,decreased gastrointestinal motility, sleep disturbances, and/or reducedpain sensitivity.

DETAILED DESCRIPTION

Described herein are methods and compositions for treating Prader-Willisyndrome by administering to a subject in need thereof a pharmaceuticalcomposition including an effective amount of a compound of Formula I,

wherein X is an ethylene, propylene, butylene or pentylene group; R isC₁₋₉ alkyl, preferably C₁₋₅ alkyl; R′ is C₁₋₉ alkyl, alkenyl or alkynyl;Y is hydrogen, halide such as chloro, fluoro, iodo or bromo,hydroxyC₁₋₄alkyl, amino, C₁₋₄alkylamino, acetylamino or thio; and Z ishydrogen, halide such as chloro, fluoro, iodo or bromo, hydroxyC₁₋₄alkyl, amino, C₁₋₄ alkylamino, acetylamino or thio, or apharmaceutically acceptable salt thereof.

In embodiments, X may be an ethylene, propylene, butylene, or pentylenegroup and R is methyl, R′ is butyl, Y is hydrogen and Z is hydrogen; orR is C₁₋₉ alkyl, C₁₋₅ alkyl, and R′ is butyl, X is ethylene, Y ishydrogen and Z is hydrogen.

In embodiments, Y may be hydrogen, halide such as chloro, fluoro, iodoor bromo, hydroxyC₁₋₄alkyl, amino, C₁₋₄alkylamino, acetylamino, thio andR is methyl, R′ is butyl, X is ethylene and Z is hydrogen.

In embodiments, Z may be hydrogen, halide such as chloro, fluoro, iodoor bromo, hydroxyC₁₋₄alkyl, amino, C₁₋₄alkylamino, acetylamino, thio andR is methyl, R′ is butyl, X is ethylene and Y is hydrogen.

In embodiments, R′ may be C₁₋₉ alkyl, alkenyl or alkynyl and R ismethyl, X is ethylene, Y is hydrogen and Z is hydrogen.

In embodiments, methods and compositions for treating Prader-WilliSyndrome include administering to a subject in need thereof apharmaceutical composition including an effective amount of a compoundof Formula II,

also known as2-[(4-butylsulfanylphenyl)-phenylmethyl]sulfanyl-N,N-dimethylethanamine(captodiamine), or a pharmaceutically acceptable salt thereof.

The chemical formula for captodiamine is C₂₁H₂₉NS₂ and its CAS number is486-17-9. The compound is also known under the following synonyms:2-[(p-(Butylthio)-alpha-phenylbenzyl)thio)-N,N-dimethylethylamine,4-06-00-06672 (Beilstein Handbook Reference), 486-17-9, BRN 2625367,Captodiame, Captodiamin, Captodiamine, Captodiamo [INN-Spanish],Captodiamum [INN-Latin], Captodramin, Captodramine, Covatin, Covatix,EINECS 207-629-1, Ethanamine,24(4-(butylthio)phenyl)phenylmethyl)thio)-N,N-dimethyl-(9CI),Ethanamine, 2-[[[4-(butylthio)phenyl]phenylmethyl]thio]-N,N-dimethyl-,ETHYLAMINE, 2-[(p-(BUTYLTHIO)-alpha-PHENYLBENZYL)THIO)-N,N-DIMETHYL-,Kaptodiamin [Czech], N 68,p-Butylmercaptobenzhydryl-beta-dimethylamino-ethylsulphide, VUFB2350.

Symptoms of Prader-Willi syndrome include hypotonia, difficulty insucking, difficulty in feeding, poor muscle tone, growth hormonedeficiency, low levels of sex hormones, a constant feeling of hunger,excessive appetite (hyperphagia), weight gain, obesity, short stature,poor motor skills, underdeveloped sex organs, intellectual disability,learning disability, delayed speech development, delayed languagedevelopment, infertility, cognitive rigidity, cognitive impairment,emotional lability, obsessive-compulsive behavior, autisticsymptomology, excessive daytime sleepiness, scoliosis,osteopenia/osteoporosis, decreased gastrointestinal motility, sleepdisturbances, and/or reduced pain sensitivity. In addition, inapproximately 10% of individuals with PWS, more severe psychiatricillness can result including psychotic episodes, depression and bipolardisorder with psychosis.

Criteria regarding learning disorders are provided in the DSM-5 thatconsiders specific learning disabilities to be a type ofneurodevelopmental disorder that impedes the ability to learn or usespecific academic skills (e.g., reading, writing, or arithmetic), whichare the foundation for other learning.

Cognitive impairment may be measured against normal cognitive function,which refers to the normal physiologic activity of the brain, including,but not limited to, one or more of the following: mental stability,memory/recall abilities, problem solving abilities, reasoning abilities,thinking abilities, judging abilities, ability to discriminate or makechoices, capacity for learning, ease of learning, perception, intuition,attention, and awareness, as measured by any criteria suitable in theart.

Cognitive impairment also includes deficits in mental activities thatare mild or that otherwise do not significantly interfere with dailylife. Mild cognitive impairment (MCI) is an example of such a condition.A patient with mild cognitive impairment may display symptoms ofdementia (e.g., difficulties with language or memory) but the severityof these symptoms is such that a diagnosis of dementia may not beappropriate.

One skilled in the art will appreciate that there are numerous human andanimal models that may be used to evaluate and compare the relativesafety and efficacy of compounds according to Formula I such ascaptodiamine or pharmaceutically acceptable salts thereof for thetreatment of cognitive impairment. In humans, cognitive function may bemeasured, for example and without limitation, by the clinical globalimpression of change scale (CGI); the Mini Mental State Exam (MMSE) (akathe Folstein Test); the Neuropsychiatric Inventory (NPI); the ClinicalDementia Rating Scale (CDR); the Cambridge Neuropsychological TestAutomated Battery (CANTAB), the Sandoz Clinical Assessment-Geriatric(SCAG) scale, the Benton Visual Retention Test (BVRT), MontrealCognitive Assessment (MoCA) or Digit Symbol Substitution Test (DSST).

In animal model systems, cognitive function may be measured in variousconventional ways known in the art, including using a Morris WaterNavigation Task, Barnes maze, radial arm maze task, T maze and the like.Other tests known in the art may also be used to assess cognitivefunction, such as novel object recognition and odor recognition tasks.

Cognitive function may also be measured using imaging techniques such asPositron Emission Tomography (PET), functional magnetic resonanceimaging (fMRI), Single Photon Emission Computed Tomography (SPECT), orany other imaging technique that allows one to measure brain function.In animals, cognitive function may also be measured withelectrophysiological techniques.

Accordingly, a compound of Formula I, such as captodiamine, or apharmaceutically acceptable salt thereof is used to treat a subjecthaving Prader-Willi syndrome. The subject may be an animal, e.g.,mammal, e.g., human, etc. As used herein, the terms “treat”, “treatment”or “treating” encompass any manner in which the symptoms or pathology ofa condition, disorder or disease associated with Prader-Willi syndromeare ameliorated or otherwise beneficially altered. In embodiments,“treat”, “treatment” or “treating” can refer to inhibiting a disease orcondition, e.g., arresting or reducing its development or at least oneclinical or subclinical symptom thereof. In embodiments, “treat”,“treatment” or “treating” can refer to relieving the disease orcondition, e.g., causing regression of the disease or condition or atleast one of its clinical or subclinical symptoms. In embodiments,“treating cognitive impairment” means ameliorating, beneficiallyaltering and/or providing relief from one or more of the symptoms ofcognitive impairment. The benefit to a subject being treated may bestatistically significant, mathematically significant, or at leastperceptible to the subject and/or the physician.

In embodiments, the terms “effective amount” or “therapeuticallyeffective amount” refer to an amount of a compound, material,composition, medicament, or other material that is effective to achievea particular pharmacological and/or physiologic effect in connectionwith PWS symptoms such as, but not limited to, one or more of thefollowing: reducing or eliminating difficulty in sucking, reducing oreliminating difficulty in feeding, reducing or eliminating poor muscletone, reducing or eliminating growth hormone deficiency, increasinglevels of sex hormones, reducing or eliminating a constant feeling ofhunger, reducing or eliminating excessive appetite (hyperphagia),reducing or eliminating weight gain, reducing or eliminating obesity,reducing or eliminating short stature, increasing motor skills, reducingor eliminating underdeveloped sex organs, reducing or eliminatingintellectual disability, reducing or eliminating learning disability,reducing or eliminating delayed speech development, reducing oreliminating delayed language development, reducing or eliminatinginfertility, reducing or eliminating cognitive rigidity, reducing oreliminating cognitive impairment, reducing or eliminating emotionallability, reducing or eliminating obsessive-compulsive behavior,reducing or eliminating autistic symptomology, reducing or eliminatingpsychotic episodes, reducing or eliminating bipolar disorder withpsychosis, reducing or eliminating excessive daytime sleepiness,reducing or eliminating scoliosis, reducing or eliminatingosteopenia/osteoporosis, reducing or eliminating decreasedgastrointestinal motility, reducing or eliminating sleep disturbances,and/or reducing or eliminating reduced pain sensitivity, enhancingcognitive function, increasing daytime activity, improving learning(either the rate or ease of learning), improving attention, improvingsocial behavior, and/or improving cerebrovascular function. Inembodiments, effective amount refers to an amount which may be suitableto prevent a decline in any one or more of the above qualities, or, inembodiments, to improve any one or more of the above qualities, forexample, constant feeling of hunger, excessive appetite (hyperphagia),weight gain, obesity, cognitive function or performance, learning rateor ability, problem solving ability, attention span and ability to focuson a task or problem, social behavior, and the like. In embodiments, aneffective amount may be suitable to reduce either the extent or rate ofdecline in a subject's appetite dysregulation, weight loss, cognitiveskills or functioning, and/or the effective amount may be suitable todelay the onset of such decline. In embodiments, an effective amountincreases hypothalamic BDNF expression. Such effectiveness may beachieved, for example, by administering compositions described herein toan individual or to a population. In embodiments, the reduction, ordelay of such a decline, or the improvement in an individual orpopulation can be relative to a cohort, e.g., a control subject or acohort population that has not received the treatment, or beenadministered the composition or medicament.

The dosage amount can vary according to a variety of factors such assubject-dependent variables (e.g., age, immune system, health, etc.),the disease or disorder being treated, as well as the route ofadministration and the pharmacokinetics of the agent being administered.

In embodiments, methods include treating PWS by administering to apatient in need thereof a pharmaceutical composition including about0.01 mg to about 1000 mg of a compound of Formula I, such ascaptodiamine, or a pharmaceutically acceptable salt thereof. Inembodiments, doses may be, e.g., in the range of about 0.1 to 1500 mg,0.1 to 1250 mg, 0.1 to 1000 mg, 0.1 to 750 mg, 0.1 to 500 mg, 0.1 to 450mg, 0.1 to 300 mg, 0.1 to 250 mg, 0.1 to 200 mg, 0.1 to 175 mg, 0.1 to150 mg, 0.1 to 125 mg, 0.1 to 100 mg, 0.1 to 75 mg, 0.1 to 50 mg, 0.1 to30 mg, 0.1 to 25 mg, 0.1 to 20 mg, 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to 5mg, 0.1 to 1 mg, 1 to 1500 mg, 1 to 1000 mg, 1 to 500 mg, 1 to 300 mg, 1to 250 mg, 1 to 200 mg, 1 to 175 mg, 1 to 150 mg, 1 to 125 mg, 1 to 100mg, 1 to 75 mg, 1 to 50 mg, 1 to 30 mg, 1 to 25 mg, 1 to 20 mg, 1 to 15mg, 1 to 10 mg, 1 to 5 mg, 5 to 1500 mg, 5 to 1000 mg, 5 to 500 mg, 5 to300 mg, 5 to 250 mg, 5 to 200 mg, 5 to 175 mg, 5 to 150 mg, 5 to 125 mg,5 to 100 mg, 5 to 75 mg, 5 to 50 mg, 5 to 30 mg, 5 to 25 mg, 5 to 20 mg,5 to 15 mg, 5 to 10 mg, 10 to 1500 mg, 10 to 1000 mg, 10 to 500 mg, 10to 300 mg, 10 to 250 mg, 10 to 200 mg, 10 to 175 mg, 10 to 150 mg, 10 to125 mg, 10 to 100 mg, 10 to 75 mg, 10 to 50 mg, 10 to 30 mg, 10 to 25mg, 10 to 20 mg, 10 to 15 mg, 15 to 1500 mg, 15 to 1000 mg, 15 to 500mg, 15 to 300 mg, 15 to 250 mg, 15 to 200 mg, 15 to 175 mg, 15 to 150mg, 15 to 125 mg, 15 to 100 mg, 15 to 75 mg, 15 to 50 mg, 15 to 30 mg,15 to 25 mg, 15 to 20 mg, 20 to 1500 mg, 20 to 1000 mg, 20 to 500 mg, 20to 300 mg, 20 to 250 mg, 20 to 200 mg, 20 to 175 mg, 20 to 150 mg, 20 to125 mg, 20 to 100 mg, 20 to 75 mg, 20 to 50 mg, 20 to 30 mg, 20 to 25mg, 25 to 1500 mg, 25 to 1000 mg, 25 to 500 mg, 25 to 300 mg, 25 to 250mg, 25 to 200 mg, 25 to 175 mg, 25 to 150 mg, 25 to 125 mg, 25 to 100mg, 25 to 75 mg, 25 to 50 mg, 25 to 30 mg, 30 to 1500 mg, 30 to 1000 mg,30 to 500 mg, 30 to 300 mg, 30 to 250 mg, 30 to 200 mg, 30 to 175 mg, 30to 150 mg, 30 to 125 mg, 30 to 100 mg, 30 to 75 mg, 30 to 50 mg, 35 to1500 mg, 35 to 1000 mg, 35 to 500 mg, 35 to 300 mg, 35 to 250 mg, 35 to200 mg, 35 to 175 mg, 35 to 150 mg, 35 to 125 mg, 35 to 100 mg, 35 to 75mg, 35 to 50 mg, 40 to 1500 mg, 40 to 1000 mg, 40 to 500 mg, 40 to 300mg, 40 to 250 mg, 40 to 200 mg, 40 to 175 mg, 40 to 150 mg, 40 to 125mg, 40 to 100 mg, 40 to 75 mg, 40 to 50 mg, 50 to 1500 mg, 50 to 1000mg, 50 to 500 mg, 50 to 300 mg, 50 to 250 mg, 50 to 200 mg, 50 to 175mg, 50 to 150 mg, 50 to 125 mg, 50 to 100 mg, 50 to 75 mg, 75 to 1500mg, 75 to 1000 mg, 75 to 500 mg, 75 to 300 mg, 75 to 250 mg, 75 to 200mg, 75 to 175 mg, 75 to 150 mg, 75 to 125 mg, 75 to 100 mg, 100 to 1500mg, 100 to 1000 mg, 100 to 500 mg, 100 to 300 mg, 100 to 250 mg, 100 to200 mg, 100 to 175 mg, 100 to 150 mg, 100 to 125 mg, 125 to 1500 mg, 125to 1000 mg, 125 to 500 mg, 125 to 300 mg, 125 to 250 mg, 125 to 200 mg,125 to 175 mg, 125 to 150 mg, 150 to 1500 mg, 150 to 1000 mg, 150 to 500mg, 150 to 300 mg, 150 to 250 mg, 150 to 200 mg, 150 to 175 mg, 175 to1500 mg, 175 to 1000 mg, 175 to 500 mg, 175 to 300 mg, 175 to 250 mg,175 to 200 mg, 200 to 1500 mg, 200 to 1000 mg, 200 to 500 mg, 200 to 300mg, 200 to 250 mg, 250 to 1500 mg, 250 to 1000 mg, 250 to 500 mg, 250 to300 mg, 7.5 to 15 mg, 2.5 to 5 mg, 1 to 5 mg, with doses of, e.g., about0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2.0 mg, 2.5mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg,30, mg, 35 mg, 40 mg, 45 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 400 mg and 500 mg beingexamples.

In embodiments, pharmaceutical compositions may include a compound ofFormula I, such as captodiamine, or a pharmaceutically acceptable saltthereof in an amount of, e.g., about 0.01 to 500 mg, 0.1 to 500 mg, 0.1to 450 mg, 0.1 to 300 mg, 0.1 to 250 mg, 0.1 to 200 mg, 0.1 to 175 mg,0.1 to 150 mg, 0.1 to 125 mg, 0.1 to 100 mg, 0.1 to 75 mg, 0.1 to 50 mg,0.1 to 30 mg, 0.1 to 25 mg, 0.1 to 20 mg, 0.1 to 15 mg, 0.1 to 10 mg,0.1 to 5 mg, 0.1 to 1 mg, 0.5 to 500 mg, 0.5 to 450 mg, 0.5 to 300 mg,0.5 to 250 mg, 0.5 to 200 mg, 0.5 to 175 mg, 0.5 to 150 mg, 0.5 to 125mg, 0.5 to 100 mg, 0.5 to 75 mg, 0.5 to 50 mg, 0.5 to 30 mg, 0.5 to 25mg, 0.5 to 20 mg, 0.5 to 15 mg, 0.5 to 10 mg, 0.5 to 5 mg, 0.5 to 1 mg,1 to 500 mg, 1 to 450 mg, 1 to 300 mg, 1 to 250 mg, 1 to 200 mg, 1 to175 mg, 1 to 150 mg, 1 to 125 mg, 1 to 100 mg, 1 to 75 mg, 1 to 50 mg, 1to 30 mg, 1 to 25 mg, 1 to 20 mg, 1 to 15 mg, 1 to 10 mg, 1 to 5 mg, 5to 500 mg, 5 to 450 mg, 5 to 300 mg, 5 to 250 mg, 5 to 200 mg, 5 to 175mg, 5 to 150 mg, 5 to 125 mg, 5 to 100 mg, 5 to 75 mg, 5 to 50 mg, 5 to30 mg, 5 to 25 mg, 5 to 20 mg, 5 to 15 mg, 5 to 10 mg, 10 to 500 mg, 10to 450 mg, 10 to 300 mg, 10 to 250 mg, 10 to 200 mg, 10 to 175 mg, 10 to150 mg, 10 to 125 mg, 10 to 100 mg, 10 to 75 mg, 10 to 50 mg, 10 to 30mg, 10 to 25 mg, 10 to 20 mg, 10 to 15 mg, 15 to 500 mg, 15 to 450 mg,15 to 300 mg, 15 to 250 mg, 15 to 200 mg, 15 to 175 mg, 15 to 150 mg, 15to 125 mg, 15 to 100 mg, 15 to 75 mg, 15 to 50 mg, 15 to 30 mg, 15 to 25mg, 15 to 20 mg, 20 to 500 mg, 20 to 450 mg, 20 to 300 mg, 20 to 250 mg,20 to 200 mg, 20 to 175 mg, 20 to 150 mg, 20 to 125 mg, 20 to 100 mg, 20to 75 mg, 20 to 50 mg, 20 to 30 mg, 20 to 25 mg, 25 to 500 mg, 25 to 450mg, 25 to 300 mg, 25 to 250 mg, 25 to 200 mg, 25 to 175 mg, 25 to 150mg, 25 to 125 mg, 25 to 100 mg, 25 to 75 mg, 25 to 50 mg, 25 to 30 mg,30 to 500 mg, 30 to 450 mg, 30 to 300 mg, 30 to 250 mg, 30 to 200 mg, 30to 175 mg, 30 to 150 mg, 30 to 125 mg, 30 to 100 mg, 30 to 75 mg, 30 to50 mg, 40 to 500 mg, 40 to 450 mg, 40 to 400 mg, 40 to 250 mg, 40 to 200mg, 40 to 175 mg, 40 to 150 mg, 40 to 125 mg, 40 to 100 mg, 40 to 75 mg,40 to 50 mg, 50 to 500 mg, 50 to 450 mg, 50 to 300 mg, 50 to 250 mg, 50to 200 mg, 50 to 175 mg, 50 to 150 mg, 50 to 125 mg, 50 to 100 mg, 50 to75 mg, 75 to 500 mg, 75 to 450 mg, 75 to 300 mg, 75 to 250 mg, 75 to 200mg, 75 to 175 mg, 75 to 150 mg, 75 to 125 mg, 75 to 100 mg, 100 to 500mg, 100 to 450 mg, 100 to 300 mg, 100 to 250 mg, 100 to 200 mg, 100 to175 mg, 100 to 150 mg, 100 to 125 mg, 125 to 500 mg, 125 to 450 mg, 125to 300 mg, 125 to 250 mg, 125 to 200 mg, 125 to 175 mg, 125 to 150 mg,150 to 500 mg, 150 to 450 mg, 150 to 300 mg, 150 to 250 mg, 150 to 200mg, 200 to 500 mg, 200 to 450 mg, 200 to 300 mg, 200 to 250 mg, 250 to500 mg, 250 to 450 mg, 250 to 300 mg, 300 to 500 mg, 300 to 450 mg, 300to 400 mg, 300 to 350 mg, 350 to 500 mg, 350 to 450 mg, 350 to 400 mg,400 to 500 mg, 400 to 450 mg, with 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg,55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg,125 mg, 150 mg 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg,350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, and 500 mg beingexamples.

Typically, dosages may be administered to a subject once, twice, threeor four times daily, every other day, once weekly, or once a month. Inembodiments, a compound of Formula I, such as captodiamine, or apharmaceutically acceptable salt thereof is administered to a subjectthree times a day (e.g., at breakfast, lunch, and dinner), at a dose of50 mg/administration (e.g., 150 mg/day). In embodiments, a compound ofFormula I, such as captodiamine, or a pharmaceutically acceptable saltthereof is administered to a subject 250 mg/per day in one or moredoses.

In embodiments, the dosage of a compound of Formula I, such ascaptodiamine, or a pharmaceutically acceptable salt thereof is 0.01-100mg/kg, 0.5-50 mg/kg, 0.5-10 mg/kg or 25-50 mg/kg once, twice, threetimes or four times daily. For example, in embodiments, the dosage is0.5 mg/kg, 1 mg/kg, 5 mg/kg, 7.5 mg/kg, or 10 mg/kg once, twice, threetimes or four times daily. In embodiments, a subject is administered atotal daily dose of 0.01 mg to 1500 mg of a compound of Formula I, suchas captodiamine, or a pharmaceutically acceptable salt thereof once,twice, three times, four times daily. In embodiments, the total amountadministered to a subject in 24-hour period is, e.g., 1 mg, 5 mg, 10 mg,25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475mg, or 500 mg. In embodiments, the subject may be started at a low doseand the dosage is escalated.

Suitable dosage forms for of a compound of Formula I, such ascaptodiamine, or a pharmaceutically acceptable salt thereof include, butare not limited to oral forms, such as tablets, hard or soft gelatincapsules, powders, granules and oral solutions, syrups or suspensions,troches, as well as the sublingual, buccal, intratracheal, intraocular,intranasal forms, forms adapted to inhalation, topical, transdermal,rectal forms such as suppositories, and implants for release ofmedication, parenteral forms, for example, intravenous, intra-arterial,intraperitoneal, intrathecal, intraventricular, intraurethrally,intrasternal, intracranial, intramuscularly or subcutaneously. Inembodiments, for such parenteral administration, it may be in the formof a sterile aqueous solution which may contain other substances, forexample, enough salts or glucose to make the solution isotonic withblood. The aqueous solutions should be suitably buffered (preferably toa pH of from 3 to 9), if necessary. The preparation of suitableparenteral formulations under sterile conditions is readily accomplishedby standard pharmaceutical techniques well-known to those skilled in theart.

Pharmaceutical compositions herein may be provided with immediaterelease, delayed release, extended release, or modified releaseprofiles. In embodiments, a delayed release dosage form is one thatreleases a drug (or drugs) at a time other than promptly afteradministration. In embodiments, an extended release dosage form is onethat allows at least a twofold reduction in dosing frequency as comparedto that drug presented as a conventional dosage form (e.g. as a solutionor prompt drug-releasing, conventional solid dosage form). Inembodiments, a modified release dosage form is one for which the drugrelease characteristics of time course and/or location are chosen toaccomplish therapeutic or convenience objectives not offered byconventional dosage forms such as solutions, ointments, or promptlydissolving dosage forms. Delayed release and extended release dosageforms and their combinations may be considered as types of modifiedrelease dosage forms.

In embodiments, pharmaceutical compositions with different drug releaseprofiles may be combined to create a two-phase or three-phase releaseprofile. For example, pharmaceutical compositions may be provided withan immediate release and an extended release profile. In embodiments,pharmaceutical compositions may be provided with an extended release anddelayed release profile. Such composition may be provided as pulsatileformulations, multilayer tablets, or capsules containing tablets, beads,granules, etc. Compositions may be prepared using a pharmaceuticallyacceptable “carrier” composed of materials that are considered safe andeffective. The “carrier” includes all components present in thepharmaceutical formulation other than the active ingredient oringredients. The term “carrier” includes, but is not limited to,diluents, binders, lubricants, glidants, disintegrants, fillers, andcoating compositions.

As used herein, the term “pharmaceutically acceptable” refers tomolecular entities and compositions that are “generally regarded assafe”, e.g., that are physiologically tolerable and do not typicallyproduce an allergic or similar untoward reaction when administered to ahuman. In embodiments, this term refers to molecular entities andcompositions approved by a regulatory agency of the federal or a stategovernment, as the GRAS list under section 204(s) and 409 of the FederalFood, Drug and Cosmetic Act, that is subject to premarket review andapproval by the FDA or similar lists, the U.S. Pharmacopeia or anothergenerally recognized pharmacopeia for use in animals, and moreparticularly in humans.

As used herein, the term “pharmaceutically acceptable salts” includesacid addition salts, addition salts of free bases, wherein the compoundis modified by making acid or base salts thereof. Examples ofpharmaceutically acceptable salts include but are not limited to mineralor organic acid salts of basic residues such as amines, and alkali ororganic salts of acidic residues such as carboxylic acids.Pharmaceutically acceptable salts include conventional non-toxic saltsor quaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. Such conventional non-toxicsalts include those derived from inorganic acids such as hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids; and thesalts prepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,sulfanilic, 2-acetoxybenzoic, fumaric, tolunesulfonic,naphthalenesulfonic, methanesulfonic, ethane disulfonic, and oxalicsalts. In embodiments, eplivanserin or pharmaceutically acceptable saltsmay include a hemifumarate salt. The pharmaceutically acceptable saltsof a compound of Formula I, such as captodiamine, can be synthesizedfrom the parent compound, which contains a basic or acidic moiety, byconventional chemical methods.

The terms “about” or “approximately” as used herein mean within anacceptable error range for the particular value as determined by one ofordinary skill in the art, which will depend in part on how the value ismeasured or determined, i.e., the limitations of the measurement system.For example, “about” can mean within 3 or more than 3 standarddeviations, per the practice in the art. Alternatively, “about” can meana range of up to 20%, a range up to 10%, a range up to 5%, and/or arange up to 1% of a given value. Alternatively, particularly withrespect to biological systems or processes, the term can mean within anorder of magnitude, e.g., within 5-fold, or within 2-fold, of a value.“About” and “approximately” are used interchangeably herein.

The compounds of Formula I or Formula II may be racemic compounds ofFormula I or II and/or optically active isomers thereof. In this regard,some of the compounds of Formula I and the compound of Formula II canhave asymmetric carbon atoms, and therefore, can exist either as racemicmixtures or as individual optical isomers (enantiomers). Compoundsdescribed herein that contain a chiral center include all possiblestereoisomers of the compound, including compositions including theracemic mixture of the two enantiomers, as well as compositionsincluding each enantiomer individually, substantially free of the otherenantiomer. Thus, for example, contemplated herein is a compositionincluding the S enantiomer of a compound substantially free of the Renantiomer, or the R enantiomer substantially free of the S enantiomer.If the named compound includes more than one chiral center, the scope ofthe present disclosure also includes compositions including mixtures ofvarying proportions between the diastereomers, as well as compositionsincluding one or more diastereomers substantially free of one or more ofthe other diastereomers. By “substantially free” it is meant that thecomposition includes less than 25%, 15%, 10%, 8%, 5%, 3%, or less than1% of the minor enantiomer or diastereomer(s).

Methods for synthesizing, isolating, preparing, and administeringvarious stereoisomers are known in the art. Separation ofdiastereoisomers or cis and trans isomers may be achieved byconventional techniques, such as, for example, by fractionalcrystallisation, chromatography or High Performance LiquidChromatography (HPLC) of a stereoisomeric mixture of the agent or asuitable salt or derivative thereof. An individual enantiomer of acompound of Formula I, such as captodiamine, may also be prepared from acorresponding optically pure intermediate or by resolution, such as byHPLC of the corresponding racemate using a suitable chiral support or byfractional crystallisation of the diastereoisomeric salts formed byreaction of the corresponding racemate with a suitable optically activeacid or base, as appropriate.

The following examples are included to augment the disclosure herein andshould not be construed as limiting in any sense.

EXAMPLES Example 1 Assessment of Effects of Captodiamine

This study, conducted by Mercier-Guyon, et al., supra, was a controlled,randomized, double-blind trial of captodiamine versus placebo conductedin 81 subjects presenting mild to moderate anxiety and treated for atleast 6 months with a stable dose of benzodiazepine. The mean age of theincluded subjects was 40.5 years and men and women were equallyrepresented. The study lasted ten weeks, including six weeksexperimental treatment, divided into four phases. The first phase lasted15 days, the second phase lasted 15 days, the third phase lasted 30 daysand the fourth phase lasted 15 days. During the study, each subject wasgradually weaned from benzodiazepines over a 14 day period using atapering dose schedule and received captodiamine (150 mg/d) or placebofor 45 days from the beginning of the weaning period. The first phase,i.e., a run-in period, started with the screening visit when entrycriteria were verified and informed consent was obtained. During therun-in period, no modification of drug treatment was made. At the end ofthis period, subjects were randomized either to placebo or captodiamineand treatment initiated for the following six weeks. Captodiamine wasgiven as three 50 mg tablets per day. During the following two weeks(the second phase, i.e., weaning phase, designated as starting at D0),each subject was individually weaned from benzodiazepine treatment,reducing benzodiazepines consumption to zero within this time, and aminimum regimen proposed, with half the dose being given during thefirst week followed by a quarter of the dose for the second week andthen discontinuation at D14 of the second phase. During the third phase(assessment phase), subjects continued captodiamine or placebo treatmentin the absence of benzodiazepines. From the assessment visit at the endof the assessment phase until the final study visit at the end of thefourth phase (post-treatment phase), all treatment was discontinued.Outcome assessments were made at D0, D15, D21, D45 and D 60. The primaryoutcome criterion was the extent of withdrawal symptoms over thetreatment period as assessed with the Tyrer Benzodiazepine WithdrawalSymptom Questionnaire (BWSQ).

During the two week weaning phase when benzodiazepines werediscontinued, withdrawal symptoms emerged in both treatment groups.Analysis of the primary outcome criterion, the Tyrer BWSQ score,revealed a statistically significant difference (p<0.0001; ANCOVA withrepeated measures) between the two study groups in favor of captodiamineattesting to a decrease in the number and intensity of withdrawalsymptoms. For the anxiety scale, the self-reported anxiety scores rosein the placebo group during the weaning and assessment phases beforereturning to baseline at the end of the post-treatment period. Incontrast, in the captodiamine treatment group, anxiety scores evolvedlittle during the weaning phase and then fell during the assessmentphase. There was a significant difference in scores between the twotreatment groups at all observation points during the experimentalphases of the study. For the drowsiness score, the scores for theplacebo group remained stable during the weaning phase and then declinedslightly, whereas they declined from D0 for the captodiamine group.Again, all inter-group differences were statistically significant duringthe experimental phases of the study. Once captodiamine treatment wasstopped after 45 days, there was no re-emergence of anxiety or evidencefor withdrawal symptoms.

Example 2 Experimental Protocol for Behavioral Evaluation ofCaptodiamine

This excerpted study, more fully reported in U.S. Pat. No. 8,461,389,involved three separate cohorts of C57B16 mice that were employed in thebehavioral evaluation of captodiamine.

Materials and Methods I

Cohort 1 was used to evaluate the drug effect on prepulse inhibition,spatial learning, open-field and novel object recognition. Cohort 2 wasused to evaluate drug effects on the forced swim test and the elevatedX-maze. The behavioral tests were administered in sequence as per daynumber. The drug was administered by the intraperitoneal route and onthe day of training the drug was administered after the behavioralanalysis. Cohort 3 was used for analysis of growth factor (GF)expression (such as, for example, Brain Derived Neurotrophic Factor(BDNF and Glial Derived Neurotrophic Factor (GDNF).Captodiamine/UCD-0620 was administered at doses of 3 and 5 mg/kg. Thecompound was administered once daily, via the intraperitoneal route, for7 days prior to testing and the animals were drug-free at time oftraining.

Materials and Methods II

The influence of captodiamine on open-field behavior, novel objectrecognition, forced swim test and water maze spatial learning.Captodiamine was administered by the intraperitoneal route at the dosesindicated. Values were analyzed using a two way ANOVA and Student t-testand those with a p values<0.05 were accepted as significant and whereappropriate are indicated with an asterisk.

Materials and Methods III

Analysis of receptor affinities was performed by Novascreen™ and thosedisplacing >20% of the natural ligand are indicated by the filled boxes.Blood levels of captodiamine were determined by GC mass spectroscopy. Inseparate samples taken from a cannulated jugular at increasing timeintervals following a single intraperitoneal injection of the drug (5mg/kg). Growth factor analysis was performed using tissue homogenatesand ELISA assays specific for each growth factor (Promega). Values wereanalyzed using a Student t-test and those with a p value<0.05 wereaccepted as significant.

Discussion of Results I and II

Captodiamine had no influence on basal locomotion in the open-fieldparadigm. However, animals tended to spend significantly more time inthe center of the center of the arena, suggesting that captodiamineexerts an anxiolytic action. This anxiolytic action was confirmed usingthe elevated X-maze in which the treated animal spent a significantlylonger periods exploring the open arms of the maze. Captodiamineexhibited no effect on the pre-pulse inhibition paradigm clearlydemonstrating it to have little or no effect on mechanisms of sensoryprocessing. In contrast, captodiamine treated animals, at the 3 mg/kgdose, spent significantly longer investigating objects during thetraining phase, as measured by the one-tailed t-test in the Novel ObjectRecognition Task. Captodiamine was also further differentiated by itssignificant pro-cognitive action in the water maze spatial learningtask. The marked anxiolytic action of captodiamine also prompted adetermination of its potential as an antidepressant. This action wasconfirmed by the significant increase on time to immobility that wasobserved in the forced swim test. The combined effect of captodiamine onopen-field behavior and performance in the elevated X-maze suggests itto have anxiolytic actions that most likely contribute to itsprocognitive actions in water maze spatial paradigm and antidepressantactions in the forced swim test.

Results III—Receptor Affinity and Pharmacokinetics for Captodiamine

Affinities were determined by allowing a 1 μM concentration ofcaptodiamine compete for receptor binding with a reference ligand (acompound with a known affinity for the receptor in question). The amountof reference ligand that is prevented from binding to a particularreceptor is measured and this gives rise to the “percent targetinhibition” value. The higher the target inhibition value, the greaterthe affinity captodiamine has for this particular receptor as itdisplaces a greater proportion of the reference ligand. This assay is anautomated high throughput assay performed on cell lines that expressonly one type of receptor and was carried out by Novascreen(www.novascreen.com). Receptor affinity is a good starting point fordetermining the mechanism of action for a particular compound. In thiscase a greater than 90% inhibition value for the Sigma 1 receptor andthe greater than 80% inhibition value for the dopamine D3 and serotonin5HT_(2c) receptor would suggest that the effects of captodiamine arepredominantly mediated through these receptors. In contrast,captodiamine only demonstrates a greater than 20% inhibition value forthe Sigma 2 receptor. Both the dopamine D3 receptor and the 5HT_(2c)receptor show a greater than 80% inhibition value, demonstrating thatsome of the effects of captodiamine are mediated through thesereceptors.

Growth Factor Modulation

Captodiamine has no effect on Brain Derived Neurotrophic Factor (BDNF)expression levels and/or activity in either the prefrontal cortex or thehippocampus. However, captodiamine significantly increased the levels ofexpression of BDNF in the hypothalamus part of the brain. In contrast,captodiamine significantly decreased levels of expression of GDNF in theprefrontal cortex of the brain but not in either the hippocampus or thehypothalamus. The mechanism by which sigma-1 receptors modulate GDNFlevels remains to be determined.

Example 3 Prospective Assessment of the Safety and Efficacy ofCaptodiamine in Ghrelin Suppression in Individuals with Prader-WilliSyndrome

The purpose of this study is to evaluate the effect of captodiamine onlevels of ghrelin, hunger, and body weight in people with Prader-Willisyndrome. This study will be a multi-center, randomized,placebo-controlled, double blind trial in which patients meetingentrance criteria will be randomly assigned to receive placebo or activedrug. Enrolled subjects will have diagnosis of PWS confirmed bychromosome analysis (i.e. interstitial deletion of paternally-derivedchromosome 15Q, uniparental maternal disomy or other chromosome 15abnormalities), be 18 years and older, and have free T4, TSH values inthe normal range (with or without thyroxine replacement). Subjects withconfirmed hypogonadism who are corrected with adequate doses of sexsteroid replacement, will have been treated for at least 6 months priorto entry and have no change in dosages over the study period. Patientswith confirmed growth hormone deficiency who are corrected with adequatedoses of replacement, will have been treated for at least 6 months priorto entry and have no change in dosages over the study period.

After baseline tests, subjects will be administered captodiamine orplacebo for 6 months. At the end of this initial 6-month treatmentperiod and a 4-month washout period, study subjects will then crossoverto receive the alternative therapy (placebo or captodiamine) for anadditional 6 months. Subjects will be followed for 16 months total atscheduled visits: 0, 2, 6, 10, 12, and 16 months. During each of thesevisits, testing will include measuring how well glucose (sugar) isprocessed, how much energy is burned off as heat, their amount of bodyfat, levels of the hormone ghrelin, and how much food is eaten at ameal. During these study periods participants will return monthly forphysical examination and blood draw to check liver enzymes. Primaryoutcome measures are ghrelin levels (change from baseline to 6 months),appetite (change from baseline to 6 months), and body weight (changefrom baseline to 6 months). Secondary outcome measures are hormonelevels (change from baseline to 6 months), body composition (change frombaseline to 6 months), energy expenditure (change from baseline to 6months), and glucose metabolism (change from baseline to 6 months).

Example 4 Prospective Assessment of the Effect of Captodiamine on WeightGain and Body Composition in Adults with Prader-Willi Syndrome

The purpose of this study will be to evaluate the effect of captodiamineon the appetite, body weight, body fat and growth hormone level ofsubjects with PWS. This will be a double blind placebo controlledclinical trial involving a total of 18 young adults aged 18 to 35 yearswith PWS. Subjects will be selected if they have Prader Willi syndromepreviously confirmed by standard genetic testing (the DNA methylationtest) or meet the clinical diagnostic criteria as follows: the presenceof at least four of the six principal characteristics of PWS syndromeincluding 1) infantile hypotonia, 2) abnormal pubertal development, 3)obesity after early infancy, 4) dysfunctional central nervous systemperformance, 5) dysmorphic facial features, and 6) short stature. Inaddition, they must have one or more of the following characteristicscommonly associated with PWS: 1) small hands and feet, 2) skin problems,3) behavioral problems related to food, and 4) decreased painsensitivity. Subjects must have a BMI of at least 30 or more. Subjectswill be divided in to the two groups of control and intervention, andtreated with either placebo (inactive drug), or captodiamine for a totalduration of 6 months. Body weight, fat distribution, objective andsubjective assessment of the hunger, fasting blood sample formeasurement of ghrelin and leptin, serum lipids, IGF-1 (growth hormonerelated protein), insulin and glucose concentrations will be measuredupon enrollment, at 3 months, and at the end of the study. Theproportion of body fat to muscle will be determined using a radiologicaltechnique, whole body dual-energy x-ray absorptiometry (DEXA) scan, andalso by measurement of skin fold thickness, waist and hip circumferenceat the enrollment prior to the intervention, and at the end of thestudy.

Example 5 Prospective Assessment of the Effect of Captodiamine onSelf-Injurious Behavior in Adults with Prader-Willi Syndrome

Prader-Willi syndrome may be characterized by a persistent pattern ofself-injurious behavior (SIB), most notably skin picking, that resultsin frequent medical care and attention. SIB in mental retardation andrelated developmental disabilities is often monitored by behavioralobservation methods. Direct evaluation of skin lesions has been reportedto help systematically follow wounds and wound healing. The goal of thisstudy is to characterize SIB in PWS and to evaluate the efficacy ofcaptodiamine versus placebo in attenuating SIB in individuals with PWS.

This will be a double blind placebo controlled clinical trial involvingadults aged 18 to 66 years with PWS. Subjects will be selected if theyhave Prader-Willi syndrome previously confirmed due to deletion of 15q11-13 or uniparental disomy and are actively engaging skin pickingbehavior. Participants in the study will be randomized to receive eithercaptodiamine or a placebo for 6 weeks. All participants will bemonitored for SIB by observation and photographic recordings of theresultant skin lesions, by reports of group home staff, and bystandardized rating measurements of self-injury. At the end of 6 weeks,participants receiving captodiamine will receive decreasing doses ofcaptodiamine; participants receiving placebo will continue to receivethe placebo. At week 9, participants previously receiving captodiaminewill be given placebo and participants previously receiving placebo willbe given captodiamine. After 6 weeks, all participants will be enteredinto a 4-month open-label extension phase. Safety and efficacymeasurements will be assessed during the 15 study visits; in the eventof worsening SIB, the blind will be broken by the study's medicaloversight physician and, if appropriate, the participant will be placeddirectly into the 4-month open-label extension phase.

Example 6 Prospective Assessment of the Effect of Captodiamine Therapyon Developmental, Nutritional and Hormonal Regulation of Ghrelin inChildren and Young Adults with Prader-Willi Syndrome

The purpose of this study is to investigate, over a 6 month period, theeffect of captodiamine therapy on food intake, sense of hunger, bodyweight, body composition, efficiency of burning calories, biomarkers ofweight regulation and growth hormone markers in children and youngAdults with PWS. This will be a double blind placebo controlled clinicaltrial involving subjects with a diagnosis of PWS confirmed by chromosomeanalysis, ages 5 years to 21 years, BMI for age greater-than or equal to85th percentile, and free T4, thyroid stimulating hormone (TSH) valuesin the normal range (either endogenous or with thyroxine replacement).

Primary outcome measures are number of participants showing a decreasein fasting total ghrelin from baseline to 6 months of treatment withcaptodiamine or placebo, number of participants with a decrease inweight from baseline to 6 months of captodiamine or placebo therapy,number of participants with decreased BMI z-score from baseline to 6months of captodiamine or placebo therapy, number of participants withdecreased skin-fold measurements from baseline to 6 months ofcaptodiamine or placebo therapy, number of participants with decrease inhunger and food intake measured by hunger and hyperphagia byquestionnaires and parent-reported 72-hour food recall from baseline to6 months of captodiamine or placebo therapy. Multiple questionnairesconsisting of a battery of free text answer questions and food diariesare combined in order to make a behavioral assessment of theparticipants food state of hunger and food intake. There is no definedscale for this assessment. Each participants' responses and parentresponses are combined. Additional primary outcome measures are numberof participants with improved insulin regulation from baseline to 6months of captodiamine or placebo therapy. Insulin regulation will bemeasured by immunochemiluminescent assay, number of participants withimproved adiponectin regulation from baseline to 6 months of ofcaptodiamine or placebo therapy, number of participants with improvedLeptin regulation from baseline to 6 months of of captodiamine orplacebo therapy, and number of participants with improved Peptide YY(PYY) regulation from baseline to 6 months of captodiamine or placebotherapy. Secondary outcome measures are number of participants withdecreased body-composition as measured by air displacementplethysmography (BOD POD® body composition tracking system) frombaseline to 6 months of captodiamine or placebo therapy, number ofparticipants with decreased body-composition as measured by dual energyX-ray absorptiometry (DEXA) scan from baseline to 6 months ofcaptodiamine or placebo therapy measured at months 0, 3, and 6, andresting energy expenditure as measured by indirect calorimetry at months0, 3 and 6.

It should be understood that the examples and embodiments providedherein are exemplary examples embodiments. Those skilled in the art willenvision various modifications of the examples and embodiments that areconsistent with the scope of the disclosure herein. Such modificationsare intended to be encompassed by the claims.

What is claimed is:
 1. A method of treating Prader-Willi syndromecomprising administering to a subject with Prader-Willi syndrome apharmaceutical composition comprising an effective amount of a compoundaccording to Formula I

wherein X is an ethylene, propylene, butylene or pentylene group; R isC₁₋₉ alkyl, preferably C₁₋₅ alkyl; R′ is C₁₋₉ alkyl, alkenyl or alkynyl;Y is hydrogen, halide, hydroxyC₁₋₄ alkyl, amino, C₁₋₄alkylamino,acetylamino or thio; and Z is hydrogen, halide such as chloro, fluoro,iodo or bromo, hydroxyC₁₋₄ alkyl, amino, C₁₋₄ alkylamino, acetylamino orthio, or a pharmaceutically acceptable salt thereof.
 2. The method oftreating Prader-Willi syndrome according to claim 1 wherein X is anethylene, propylene, butylene, or pentylene group; R is methyl, R′ isbutyl, Y is hydrogen and Z is hydrogen; or R is C₁₋₉ alkyl, C₁₋₅ alkyl,and R′ is butyl, X is ethylene, Y is hydrogen and Z is hydrogen.
 3. Themethod of treating Prader-Willi syndrome according to claim 1 wherein Yis hydrogen, halide such as chloro, fluoro, iodo or bromo, hydroxylC₁₋₄alkyl, amino, C₁₋₄ alkylamino, acetylamino, or thio, and R ismethyl, R′ is butyl, X is ethylene and Z is hydrogen.
 4. The method oftreating Prader-Willi syndrome according to claim 1 wherein R′ is C₁₋₉alkyl, alkenyl or alkynyl, R is methyl, X is ethylene, Y is hydrogen andZ is hydrogen.
 5. The method of treating Prader-Willi syndrome accordingto claim 1 wherein the compound is captodiamine or a pharmaceuticallyacceptable salt thereof.
 6. The method of treating Prader-Willi syndromeaccording to claim 1 wherein the compound is administered in an amountof 0.01 mg to 1500 mg.
 7. The method of treating Prader-Willi syndromeaccording to claim 1 wherein captodiamine or pharmaceutically acceptablesalt thereof is administered in an amount of 0.01 mg to 1500 mg.
 8. Themethod of treating Prader-Willi syndrome according to claim 1, whereinthe composition provides improvement in at least one symptom selectedfrom the group consisting of hypotonia, difficulty in sucking,difficulty in feeding, poor muscle tone, growth hormone deficiency, lowlevels of sex hormones, a constant feeling of hunger, excessive appetite(hyperphagia), weight gain, obesity, short stature, poor motor skills,underdeveloped sex organs, intellectual disability, learning disability,delayed speech development, delayed language development, infertility,cognitive rigidity, cognitive impairment, emotional lability,obsessive-compulsive behavior, autistic symptomology, psychoticepisodes, bipolar disorder with psychosis, excessive daytime sleepiness,scoliosis, osteopenia/osteoporosis, decreased gastrointestinal motility,sleep disturbances, and reduced pain sensitivity.
 9. The method oftreating Prader-Willi syndrome according to claim 1, wherein thecomposition includes pharmaceutically acceptable adjuvants, diluentsand/or carriers.
 10. The method of treating Prader-Willi syndromeaccording to claim 1, wherein administering the composition isaccomplished via a route selected from the group consisting of oral,buccal, sublingual, rectal, topical, intranasal, and parenteral.
 11. Amethod of treating Prader-Willi syndrome comprising administering to asubject with Prader-Willi syndrome a pharmaceutical compositioncomprising an effective amount of captodiamine or a pharmaceuticallyacceptable salt thereof in an amount of from 0.01 mg to 1500 mg.
 12. Themethod of treating Prader-Willi syndrome according to claim 11, whereinthe subject is administered 1 mg to 500 mg of captodiamine or apharmaceutically acceptable salt thereof.
 13. The method of treatingPrader-Willi syndrome according to claim 11, wherein the subject isadministered 50 mg to 250 mg of captodiamine or a pharmaceuticallyacceptable salt thereof.
 14. The method of treating Prader-Willisyndrome according to claim 11, wherein the total amount of captodiamineor a pharmaceutically acceptable salt thereof administered to thesubject in a twenty-four hour period is between 1 mg and 1500 mg. 15.The method of treating Prader-Willi syndrome according to claim 11,wherein the total amount of captodiamine or a pharmaceuticallyacceptable salt thereof administered to the subject in a twenty-fourhour period is between 1 mg and 500 mg.
 16. The method of treatingPrader-Willi syndrome according to claim 11, wherein captodiamine or apharmaceutically acceptable salt thereof is administered from one tofour times a day.
 17. The method of treating Prader-Willi syndromeaccording to claim 11, wherein administering the composition isaccomplished via a route selected from the group consisting of oral,buccal, sublingual, rectal, topical, intranasal, vaginal and parenteral.18. The method of treating Prader-Willi syndrome according to claim 11,wherein the composition provides improvement in at least one symptomselected from the group consisting of hypotonia, difficulty in sucking,difficulty in feeding, poor muscle tone, growth hormone deficiency, lowlevels of sex hormones, a constant feeling of hunger, excessive appetite(hyperphagia), weight gain, obesity, short stature, poor motor skills,underdeveloped sex organs, cognitive impairment, intellectualdisability, learning disability, delayed speech development, delayedlanguage development, infertility, cognitive rigidity, emotionallability, self-injury, obsessive-compulsive behavior, autisticsymptomology, psychotic episodes, bipolar disorder with psychosis,excessive daytime sleepiness, scoliosis, osteopenia/osteoporosis,decreased gastrointestinal motility, sleep disturbances, and reducedpain sensitivity.